Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress

Knowles, Juliet K.; Helbig, Ingo; Metcalf, Cameron S.; Lubbers, Laura S.; Isom, Lori L.; Demarest, Scott; Goldberg, Ethan M.; George, Alfred L.; Lerche, Holger; Weckhuysen, Sarah; Whittemore, Vicky; Berkovic, Samuel F.; Lowenstein, Daniel H.

doi:10.1111/epi.17332

Cited by 59 publications

(50 citation statements)

References 100 publications

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“…Epilepsy is caused by excessive abnormal discharge of nerve cells in the brain. Persistent seizures can lead to oxidative stress and inflammation in the brain, damage brain tissue, and cause cognitive dysfunction ( Knowles et al, 2022 ). Puerarin is able to improve epilepsy-induced brain damage through anti-inflammatory, antioxidant, and anti-apoptotic effects, but the exact mechanism is unclear ( Xie et al, 2014 ).…”

Section: Puerarin Regulates Pi3k/akt Signal Pathway To Protect the Ne...mentioning

confidence: 99%

Protective effects and mechanism of puerarin targeting PI3K/Akt signal pathway on neurological diseases

et al. 2022

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Neurological diseases impose a tremendous and increasing burden on global health, and there is currently no curative agent. Puerarin, a natural isoflavone extracted from the dried root of Pueraria montana var. Lobata (Willd.) Sanjappa and Predeep, is an active ingredient with anti-inflammatory, antioxidant, anti-apoptotic, and autophagy-regulating effects. It has great potential in the treatment of neurological and other diseases. Phosphatidylinositol 3-kinases/protein kinase B (PI3K/Akt) signal pathway is a crucial signal transduction mechanism that regulates biological processes such as cell regeneration, apoptosis, and cognitive memory in the central nervous system, and is closely related to the pathogenesis of nervous system diseases. Accumulating evidence suggests that the excellent neuroprotective effect of puerarin may be related to the regulation of the PI3K/Akt signal pathway. Here, we summarized the main biological functions and neuroprotective effects of puerarin via activating PI3K/Akt signal pathway in neurological diseases. This paper illustrates that puerarin, as a neuroprotective agent, can protect nerve cells and delay the progression of neurological diseases through the PI3K/Akt signal pathway.

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Section: Puerarin Regulates Pi3k/akt Signal Pathway To Protect the Ne...mentioning

confidence: 99%

Protective effects and mechanism of puerarin targeting PI3K/Akt signal pathway on neurological diseases

et al. 2022

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“…Probably, genomic studies of epileptic disorders have demonstrated one of the most successful explorations of monogenic causes in a heterogeneous group of diseases. These data have been extensively used for understanding molecular mechanisms and developing treatments for this devastative condition [ 1 , 2 ]. However, in contrast to monogenic epilepsies, epileptic disorders caused by chromosomal aberrations are rarely addressed.…”

Section: Introductionmentioning

confidence: 99%

Cytogenomic epileptology

et al. 2023

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Molecular cytogenetic and cytogenomic studies have made a contribution to genetics of epilepsy. However, current genomic research of this devastative condition is generally focused on the molecular genetic aspects (i.e. gene hunting, detecting mutations in known epilepsy-associated genes, searching monogenic causes of epilepsy). Nonetheless, chromosomal abnormalities and copy number variants (CNVs) represent an important part of genetic defects causing epilepsy. Moreover, somatic chromosomal mosaicism and genome/chromosome instability seem to be a possible mechanism for a wide spectrum of epileptic conditions. This idea becomes even more attracting taking into account the potential of molecular neurocytogenetic (neurocytogenomic) studies of the epileptic brain. Unfortunately, analyses of chromosome numbers and structure in the affected brain or epileptogenic brain foci are rarely performed. Therefore, one may conclude that cytogenomic area of genomic epileptology is poorly researched. Accordingly, molecular cytogenetic and cytogenomic studies of the clinical cohorts and molecular neurocytogenetic analyses of the epileptic brain appear to be required. Here, we have performed a theoretical analysis to define the targets of the aforementioned studies and to highlight future directions for molecular cytogenetic and cytogenomic research of epileptic disorders in the widest sense. To succeed, we have formed a consortium, which is planned to perform at least a part of suggested research. Taking into account the nature of the communication, “cytogenomic epileptology” has been introduced to cover the research efforts in this field of medical genomics and epileptology. Additionally, initial results of studying cytogenomic variations in the Russian neurodevelopmental cohort are reviewed with special attention to epilepsy. In total, we have concluded that (i) epilepsy-associated cytogenomic variations require more profound research; (ii) ontological analyses of epilepsy genes affected by chromosomal rearrangements and/or CNVs with unraveling pathways implicating epilepsy-associated genes are beneficial for epileptology; (iii) molecular neurocytogenetic (neurocytogenomic) analysis of postoperative samples are warranted in patients suffering from epileptic disorders.

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“…Evidently, individual phenotypic features contain valuable information to guide variant interpretation. Knowledge of variant functional effects and genotype-phenotype correlations facilitates a timely diagnosis, informs genetic counselling, and offers therapeutic and prognostic guidance to the clinician (25). However, variant interpretation requires causal evidence generated by electrophysiological experiments which are relatively time-consuming and expensive.…”

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confidence: 99%

Learning with phenotypic similarity improves the prediction of functional effects of missense variants in voltage-gated sodium channels

Boßelmann

Hedrich

Lerche

et al. 2022

Preprint

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Background: Missense variants in genes encoding voltage-gated sodium channels are associated with a spectrum of severe diseases affecting neuronal and muscle cells, the so-called sodium channelopathies. Variant effects on the biophysical function of the channel correlate with clinical features and can in most cases be categorized as an overall gain- or loss-of-function. This information enables a timely diagnosis, facilitates precision therapy, and guides prognosis. Machine learning models may be able to rapidly generate supporting evidence by predicting variant functional effects. Methods: Here, we describe a novel multi-task multi-kernel learning framework capable of harmonizing functional results and structural information with clinical phenotypes. We included 62 sequence- and structure-based features such as amino acid physiochemical properties, substitution radicality, conservation, protein-protein interaction sites, expert annotation, and others. We harmonized phenotypes as human phenotype ontology (HPO) terms, and compared different measures of phenotypic similarity under simulated sparsity or noise. The final model was trained on whole-cell patch-clamp recordings of 375 unique non-synonymous missense variants each expressed in mammalian cells. Results: Our gain- or loss-of-function classifier outperformed both conventional baseline and state-of-the-art methods on internal validation (mean accuracy 0.837 SD 0.035, mean AU-ROC 0.890 SD 0.023) and on an independent set of recently described variants (n = 30, accuracy 0.967, AU-ROC 1.000). Model performance was robust across different phenotypic similarity measures and largely insensitive to phenotypic noise or sparsity. Localized multi-kernel learning offered biological insight and interpretability by highlighting channels with implicit genotype-phenotype correlations or latent task similarity for downstream analysis. Conclusions: Learning with phenotypic similarity makes efficient use of clinical information to enable accurate and robust prediction of variant functional effects. Our framework extends the use of human phenotype ontology terms towards kernel-based methods in machine learning. Training data, pre-trained models, and a web-based graphical user interface for the model are publicly available.

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Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress

Cited by 59 publications

References 100 publications

Protective effects and mechanism of puerarin targeting PI3K/Akt signal pathway on neurological diseases

Protective effects and mechanism of puerarin targeting PI3K/Akt signal pathway on neurological diseases

Cytogenomic epileptology

Learning with phenotypic similarity improves the prediction of functional effects of missense variants in voltage-gated sodium channels

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